Sustained release compositions comprising micronized tolcapone

ABSTRACT

The present invention relates to sustained release tablet comprising micronized tolcapone, a release retardant and a binder, to said tablet for use in the prevention and/or treatment of a transthyretin-associated amyloidosis, to a method for the prevention and/or treatment of a transthyretin-associated amyloidosis comprising administering to a subject in need thereof an effective amount of said tablet, to pharmaceutical composition in the form of said tablet which is used in the prevention and/or treatment of a transthyretin-associated amyloidosis and to a process for the manufacture of said tablet.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase application under 35 U.S.C. § 371of International Application No. PCT/EP2017/069168, filed on 28 Jul.2017, which claims the benefit of European Patent Application No.16382372.7, filed 29 Jul. 2016. The complete disclosure of each of theabove-identified applications is fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to sustained release compositionscomprising micronized tolcapone.

The therapeutic compound(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone, more commonlyknown as tolcapone, is described in U.S. Pat. No. 5,236,952.

The currently marketed formulations of tolcapone are 100 mg and 200 mgfilm coated tablets. Tolcapone is marketed in many countries under thebrand name TASMAR®. TASMAR® is a tablet which is used by oraladministration. Said tablet is manufactured through a process involvingthe granulation of tolcapone and the subsequent mixture of said granuleswith extragranular excipients. The mixture is then compressed into animmediate release tablet.

There is a need for an extended release tablet comprising tolcapone, forexample, to reduce peak plasma concentration and to maintain therapeuticplasma levels for a prolonged period of time. In particular, there is aneed for an extended release tablet comprising tolcapone which may bemanufactured by a direct compression process, i.e. a process that doesnot involve the preparation of granules comprising tolcapone and otherexcipients and the subsequent mixture of said granules withextragranular excipients prior to compression into tablets.

It is an object of the present invention to provide for a sustainedrelease formulation for tolcapone, preferably in the form of a tablet.It is a further object of the present invention to provide for asustained release formulation in the form of a tablet manufactured byusing a direct compression process. It is another object of the presentinvention to provide for a method for the prevention and/or treatment ofa transthyretin-associated amyloidosis comprising administering to asubject in need thereof the sustained release formulation of tolcapone.It is still another object of the present invention to provide for theuse of micronized tolcapone together with a release retardant and abinder for the manufacture of a medicament in the form of a tablet forthe treatment of a transthyretin-associated amyloidosis. It is stillanother object of the present invention to provide for a pharmaceuticalcomposition in the form of a sustained release tablet which is used inthe prevention and/or treatment of a transthyretin-associatedamyloidosis.

Surprisingly, it has been found that micronized tolcapone may provideadvantages for the formulation of a sustained release composition since,quite unexpectedly, compositions comprising micronized tolcapone show aslower release of the active ingredient than identical compositionswherein tolcapone is incorporated in a non-micronized form.

This is completely unexpected since it is very well known that reductionof the particle size of a product, for example by micronization, resultsin an increase of the product's specific surface area and, consequently,in an increase of the dissolution rate of said product.

Among the advantages of using micronized tolcapone in compositionsdesigned for the sustained release of said tolcapone one can cite thatthe time necessary for the release of 80% of the product may be extendedin comparison with identical formulations wherein tolcapone is used innon-micronized form.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to modified releasetablets that contain tolcapone in micronized form. The amount oftolcapone in the tablets can range from 5 to 80% by weight of thecomposition. The balance of the tablet can be made up of at least onerelease retardant. In a particular aspect of the present invention therelease retardant is a water-soluble, water swellable and/or waterinsoluble polymer. Particularly useful as release retardants arecellulose polymers such as ethylcellulose, hydroxypropyl celluloseand/or hydroxypropyl methyl cellulose. The aforementioned tablets canadvantageously be prepared through a direct compression process.

In a second aspect of the present invention, the invention features amethod for making sustained release tablets of tolcapone. In aparticular embodiment, tolcapone is mixed with a release retardant andoptionally other pharmaceutically acceptable excipients using any mixingequipment such a biconical drum. The resulting mixture can be compressedinto tablets.

In third aspect the present invention relates to a method for theprevention and/or treatment of a transthyretin-associated amyloidosiscomprising administering to a subject in need thereof an effectiveamount of a tablet according to the first aspect described above.

In a fourth aspect the present invention relates to the use ofmicronized tolcapone together with a release retardant and a binder forthe manufacture of a medicament in the form of a tablet as defined inthe first aspect for the treatment of a transthyretin-associatedamyloidosis.

In a fourth aspect the present invention relates to a pharmaceuticalcomposition in the form of a tablet as defined in the first aspect whichis used in the prevention and/or treatment of a transthyretin-associatedamyloidosis.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constituting apart of the specification, illustrates exemplary embodiments of thepresent invention.

FIG. 1 shows a chart depicting the dissolution profiles for exemplaryembodiments in accordance with the present invention as disclosed inExamples 3 and 4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to sustained release tablets of tolcaponewhich comprise tolcapone, a release retardant and to a process forpreparing such tablets. The sustained release tablets may optionallyfurther comprise binders, plasticizers, disintegrants, and/orlubricants.

As used herein the term “tablet” is intended to encompass compressedpharmaceutical dosage formulations of all shapes and sizes, whetheruncoated or coated.

As used herein the term “pharmaceutically acceptable” refers to thosecompounds, compositions and/or dosage forms, which are, within the scopeof sound medical judgment, suitable for contact with the tissues ofmammals, especially humans, without excessive toxicity, irritation,allergic response and other problem complications commensurate with areasonable benefit/risk ratio. In particular any compound which has beenapproved for human or veterinary use is a “pharmaceutically acceptable”compound.

As used herein the term “tolcapone” refers to the free phenolic form oftolcapone or a pharmaceutically acceptable salt thereof.

As used herein the terms “tolcapone in micronized form” and “micronizedtolcapone” are used indistinctively to designate a solid form oftolcapone having a D_(v,0.9) of not more than 70 μm, preferably not morethan 60 μm and most preferably not more than 55 μm. D_(v,0.9) may bedetermined according to the general method described in section 2.9.31of the European Pharmacopeia in particular using a particle size laseranalyzer MASTERSIZER 2000 from Malvern featuring a wet dispersion unitHYDRO 2000 SM for small volumes of sample.

Tolcapone is present in the tablets of the present invention in atherapeutically effective amount or concentration. Such atherapeutically effective amount or concentration is known to one ofordinary skill in the art as the amount or concentration varies with thetherapeutic compound being used and the indication which is beingaddressed. For example, in accordance with the present invention,Tolcapone may be present in an amount of 5% to 80% by weight of tablet.In one embodiment, Tolcapone may be present in an amount by weight of10% to about 70% by weight of tablet. In one embodiment, tolcapone maybe present in an amount by weight of about 20% to about 60% by weight oftablet. In one embodiment, tolcapone may be present in an amount byweight of about 30% to about 50% by weight of tablet.

As used herein, the term “sustained release” refers to the gradual butcontinuous or sustained release over a relatively extended period oftolcapone content after oral ingestion such as a slow release oftolcapone, e.g., not greater than 90%, preferably not greater than 80%within a relatively long period of time, e.g., within 3 hour, preferably4 hours and more preferably 5 hours after oral ingestion. Particularlyuseful conditions for sustained release are release of not greater than90% of tolcapone within 5 hours after oral ingestion.

Since measurement of the release of tolcapone from a tablet after oralingestion is difficult, for the purpose of the present invention, atablet is considered to exhibit a “sustained release” profile when theproportion of tolcapone dissolved after 5 hours in the conditions ofUSP36 Tolcapone monograph is not higher than 90%, preferably not higherthan 80% of the total amount of tolcapone in the tablet.

As used herein the term “release retardant” refers to any material orsubstance that slows the release of tolcapone from a tablet when orallyingested. A release retardant is typically a cellulose polymer.

As used herein the term “cellulose polymer” refers to cellulose estersand cellulose ethers (e.g., methylcellulose and ethylcellulose)hydroxyalkylcelluloses (e.g., -hydroxypropylcellulo se),hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose),cellulose phthalates (e.g., cellulose acetate phthalate andhydroxypropylmethylcellulose phthalate) and cellulose succinates (e.g.,hydroxypropylmethylcellulose succinate or hydroxypropylmethylcelluloseacetate succinate).

In an embodiment of the present invention the “release retardant” ishydroxypropylmethylcellulose.

As used herein the term “direct compression” refers to a tablettingprocess wherein the tablet or any other compressed dosage form is madeby a process comprising the steps of dry blending the components of theformulation and compressing the dry blend to form the formulation.

As used herein the term “suitable mixing equipment” is used to designatean equipment which may be used to blend solid ingredients in the absenceof any liquid or fluid ingredient. Examples of such equipment are aribbon blender, a V blender, a cone screw blender, a screw blender, adouble cone blender, a planetary mixer, a paddle mixer, a drum blender,a high shear mixer and a biconical drum.

As used herein, the term “direct compression” refers to the followingcompounding process that comprises the steps of:

-   -   (a) providing two or more solid components (such as tolcapone,        at least one release retardant, and optionally, a binder, a        lubricant and other pharmaceutically acceptable excipients)    -   (b) forming a mixture with the components of step (a) using any        suitable mixing equipment in the absence of any liquid        ingredient.    -   (c) filing the mixture of step (b) into a die and compressing it        using a punch.

As used herein the term “solid” is used to designate any material whichis solid at room temperature (25° C.).

As used herein the term “liquid” is used to designate any material whichis liquid at room temperature (25° C.).

Examples of pharmaceutically acceptable binders include, but are notlimited to, starches; celluloses and derivatives thereof, for example,microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA),sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The bindermay be present in an amount from about 0% to about 65%, e.g., 20-50% byweight of the composition.

Examples of pharmaceutically acceptable lubricants include, but are notlimited to, colloidal silica, magnesium trisilicate, starches, talc,tribasic calcium phosphate, magnesium stearate, aluminum stearate,calcium stearate, magnesium carbonate and magnesium oxide. The lubricantmay be present in an amount from about 0% to about 5% by weight of thecomposition. In one embodiment, the lubricant may be present in anamount from about 0.1% to about 1.5% by weight of composition.

In an embodiment of the present invention the tablet comprises acellulose polymer, preferably selected from the group consisting ofcellulose ethers and cellulose esters, more preferably hydroxypropylmethyl cellulose, as release retardant.

In another embodiment of the present invention the tablet comprisesmicrocrystalline cellulose as a binder.

In another embodiment of the present invention the tolcapone used in themanufacture of the tablet has a particle size distribution characterizedin that its D_(v,0.9) is not greater than 70 μm.

In another embodiment of the present invention the tablet comprises from5% to 80% by weight of tolcapone.

In another embodiment of the present invention the tablet ischaracterized in that the proportion of tolcapone dissolved after 5hours in the conditions of USP36 Tolcapone monograph is not higher than90% of the total amount of tolcapone in the tablet.

In another embodiment of the present invention the tablet ischaracterized in that it shows a release of tolcapone such that notgreater than 90% is released during the period starting with oralingestion and ending 5 hours after oral ingestion.

In another embodiment of the present invention the tolcapone used in themanufacture of the tablet has a particle size distribution characterizedin that its D_(v,0.5) is greater than 10 μm but not greater than 80 μm.

In another embodiment of the present invention the tablet comprisestolcapone, hydroxypropylmethyl cellulose and microcrystalline cellulose.

In another embodiment of the present invention the tablet comprisestolcapone, hydroxypropylmethyl cellulose, microcrystalline cellulose,talc, magnesium stearate and anhydrous colloidal silica.

In an embodiment of the present invention the tablets comprise:

-   -   a) 5 to 80% by weight, for example 14 to 41% by weight of        tolcapone    -   b) 20 to 36% of hydroxypropylmethyl cellulose such as, for        example, Methocel® K 100 M    -   c) 8 to 65% by weight, for example 36 to 49% by weight of        microcrystalline cellulose such as, for example, Vivapur® 102    -   d) 0.1 to 3% by weight, for example 0.1 to 1.4% by weight of        talc    -   e) 0.03 to 2% by weight, for example 0.03 to 0.7% by weight of        magnesium stearate    -   f) 0.06 to 0.8% by weight for example 0.26 to 0.42% by weight of        anhydrous colloidal silica

In an embodiment of the present invention the tablets weight from 750 to850 mg and comprise:

-   -   a) 50 to 500 mg, for example 250 to 350 mg of tolcapone    -   b) 160 to 280 mg, for example 160 to 260 mg of        hydroxypropylmethyl cellulose such as, for example, Methocel® K        100 M    -   c) 50 to 500 mg, for example 260 to 350 mg of microcrystalline        cellulose such as, for example, Vivapur® 102    -   d) 0.1 to 20 mg, for example 0.1 to 10 mg of talc    -   e) 0.2 to 10 mg, for example 0.4 to 6 mg of magnesium stearate    -   f) 0.6 to 6 mg, for example 2 to 3 mg of anhydrous colloidal        silica

In another aspect the present invention relates to a tablet aspreviously defined for use in the prevention and/or treatment of atransthyretin-associated amyloidosis, such as familial amyloidpolyneuropathy, senile systemic amyloidosis, leptomeningeal amyloidosis,familial amyloid cardiomyopathy.

In another aspect the present invention relates to a process for themanufacture of a tablet as defined before comprising the steps:

-   -   a) providing tolcapone, a release retardant and a binder    -   b) optionally sieving the ingredients of step a) with a mesh        having 5 mm openings    -   c) mixing the ingredients of step b)    -   d) compressing the ingredients of step c) to form tablets.

EXAMPLES

Determination of Tolcapone's Particle Size

Particle size measurement (D_(v,0.1), D_(v,05), D_(v,0.9) and D_(v,1.0))may be determined according to the general method described in section2.9.31 of the European Pharmacopeia in particular using a particle sizelaser analyzer MASTERSIZER 2000 from Malvern featuring a wet dispersionunit HYDRO 2000 SM for small volumes of sample.

Material:

-   -   Sample: Tolcapone suspension    -   Refraction index: 1.59 (default)    -   Dispersant: water for injection    -   Refraction index: 1.33

Cycles:

-   -   Measurements for each aliquot: 3    -   Lag time: 12 s    -   Pump stirring velocity: 2500 rpm

Measuring Time:

-   -   Measure: 12 s (in triplicates)    -   Measure snaps: 12000    -   Background: 10 s    -   Background snaps: 10000

Three readings are made for each sample.

Solubility Measurements

Solubility measurements are carried out using the protocol described inUS Pharmacopeia USP 36 with minor changes, such as longer time points.

The specific conditions used in the measurements were:

Medium: 900 ml of a phosphate buffer with a pH of 6.8 containing 1% ofsodium lauryl sulfate.

Apparatus 2: at 75 rpm

Time: at various intervals between 0 and 1440 minutes

Procedure: Determine the amount of Tolcapone dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 271 nm onfiltered portions of the solution under test, suitably diluted withMedium, if necessary, in comparison with a Standard solution having aknown concentration of USP Tolcapone RS in the same Medium. Calculatethe amount of tolcapone dissolved in each Tablet.

General.

In the following examples the sustained release tablets are preparedusing the following process:

-   -   1. The ingredients are weighed    -   2. The ingredients are sieved with a mesh with 5 mm openings    -   3. The ingredients are mixed in a biconical drum at a rotation        speed of 20 rpm during 10 minutes    -   4. 800 mg of the resulting mixture are compressed in an        eccentric tableting press BONALS with oblong punches measuring        19 mm×10 mm without slot.

In the following examples the particle size distribution ofnon-micronized tolcapone is characterized by the following parameters

D_(v,0.1) D_(v,0.5) D_(v,0.9) D_(v,1.0) <22.45 μm <87.23 μm <307.86 μm<1096.48 μm

In the following examples the particle size distribution of micronizedtolcapone is characterized by the following parameters

D_(v,0.1) D_(v,0.5) D_(v,0.9) D_(v,1.0) <6.09 μm <17.62 μm <54.33 μm<316.23 μm

D_(v,x) value indicates that x*100% of the volume of the particles is inparticles which are smaller than this value. Thus, D_(v,0.9) lower than54.33 μm that 90% of the volume of the particles is in particles whichare smaller 54.33 μm.

Example 1

Components weight % weight (mg) Tolcapone 37.5 300 Hydroxypropylmethyl29.0 232 cellulose⁽¹⁾ Microcrystalline cellulose⁽²⁾ 31.7 253.60 Talc 1.08 Magnesium stearate 0.5 4 Anhydrous colloidal silica⁽³⁾ 0.3 2.4 TOTAL100 800 ⁽¹⁾Methocel ® K 100 M CR ⁽²⁾Vivapur ® 102 ⁽³⁾Aerosil ® 200

Example 2

Components weight % weight (mg) Tolcapone 37.5 300 Hydroxypropylmethyl20 160 cellulose⁽¹⁾ Microcrystalline cellulose⁽²⁾ 42.03 336.24 Talc 0.120.96 Magnesium stearate 0.05 0.4 Anhydrous colloidal silica⁽³⁾ 0.3 2.4TOTAL 100 800 ⁽¹⁾Methocel ® K 100 M CR ⁽²⁾Vivapur ® 102 ⁽³⁾Aerosil ® 200

Example 3

Components weight % weight (mg) Tolcapone (non-micronized) 37.5 300Hydroxypropylmethyl 20.0 160 cellulose⁽¹⁾ Microcrystalline cellulose⁽²⁾42.03 336.24 Talc 0.12 0.96 Magnesium stearate 0.05 0.4 Anhydrouscolloidal silica⁽³⁾ 0.30 2.4 TOTAL 100 800 ⁽¹⁾Methocel ® K 100 M CR⁽²⁾Vivapur ® 102 ⁽³⁾Aerosil ® 200

Example 4

Components weight % weight (mg) Tolcapone (micronized) 37.5 300Hydroxypropylmethyl 20.0 160 cellulose⁽¹⁾ Microcrystalline cellulose⁽²⁾42.03 336.24 Talc 0.12 0.96 Magnesium stearate 0.05 0.4 Anhydrouscolloidal silica⁽³⁾ 0.30 2.4 TOTAL 100 800 ⁽¹⁾Methocel ® K 100 M CR⁽²⁾Vivapur ® 102 ⁽³⁾Aerosil ® 200

Example 5 Dissolution Profiles of the Compositions of Example 3 and 4

Solubility measurements were carried out following the protocoldescribed above under the heading “Solubility measurements”. The dataobtained were processed by s simple regression method adjusting thesedata to a potential equation [Y(% dissolved)=A·X(time)^(B)] which isoptimal to explain the evolution of the dissolution process within abounded time interval (50 to 650 minutes).

The results obtained are as follows:

Product of Example 3

Adjusted equation:Y=2.0656·X ^(0.3887)

Regression analysis-Multiplicative model: Y = a * X{circumflex over( )}b Dependent variable: (Comp3) Independent variable: (Time3)Selection variable: Time3 > 50 & Time3 < 650 Parameter EstimationStandard Error Statistical T P-Value Ordinate 2.06557 0.0289582 71.32950.0000 Slope 0.388712 0.00516411 75.2719 0.0000 Analysis of VarianceSource Square sum GL Average squar F-ratio P-Value Model 1.67318 11.67318 5665.86 0.0000 Residue 0.00590618 20 0.000295309 Total (Corr.)1.67909 21 Correlation coefficient = 0.99824 Square-R = 99.6483percentage

From the results of the analysis of variance (ANOVA) of the adjustedmodel it is observed that this explains the 99.65% of the quadraticvariation of dissolution as a function of time, resulting in acorrelation coefficient r=0.9982 between the observed values and valuesadjusted with the help of the equation. Thus, it may be concluded thatthe dissolution kinetic of the product of example 3 fits a mathematicalmodel of simple potential regression with a coefficient A=2.0656 and apower B=0.3887.

Product of Example 4

Adjusted equation: Y=1.6295·X ^(0.4347)

Regression analysis-Multiplicative model: Y = a * X{circumflex over( )}b Dependent variable: (Comp4) Independent variable: (Time4)Selection variable: Time4 > 50 & Time4 < 650 Parameter EstimationStandard Error Statistical T P-Value Ordinate 1.62945 0.0287 56.77530.0000 Slope 0.434735 0.00513096 84.7279 0.0000 Analysis of VarianceSource Square sum GL Average squar F-ratio P-Value Model 1.95026 11.95026 7178.81 0.0000 Residue 0.00543337 20 0.000271669 Total (Corr.)1.95569 21 Correlation coefficient = 0.99861 Square-R = 99.7222percentage

From the results of the analysis of variance (ANOVA) of the adjustedmodel it is observed that this explains the 99.72% of the quadraticvariation of dissolution as a function of time, resulting in acorrelation coefficient r=0.9986 between the observed values and valuesadjusted with the help of the equation. Thus, it may be concluded thatthe dissolution kinetic of the product of example 4 fits a mathematicalmodel of simple potential regression with a coefficient A=1.6295 and apower B=0.4347.

Comparison Between the Dissolution Profiles of the Compositions ofExamples 3 and 4 Adjusted to the Potential Lineal Regression

A comparative statistical study is carried out based on confidenceintervals at 95% for each experimental value to determine whether thereexist statistically significant differences between the kinetics ofdissolution of the formulations of examples 3 and 4 within the timeinterval of 50 minutes to 650 minutes. Insofar as these intervals do notoverlap each other (which can be seen when plotting said predictionintervals), it can be concluded that there are significant differencesbetween the kinetics of dissolution obtained for each of theformulations.

The representation of the experimental values and the adjusted modelsand prediction intervals for a confidence interval of 95% is presentedin FIG. 1 .

It is noted that for the entire experimental range studied, the adjusteddissolution values for the composition of example 3 are, with aconfidence interval of 95%, higher than those for the composition ofexample 4. Thus, it may be concluded that the composition of example 3(comprising non-micronized tolcapone) shows a higher dissolution ratethan that of the composition of example 4 (comprising micronizedtolcapone).

The invention claimed is:
 1. A sustained release solid tablet for oraladministration comprising (a) from 50-500 mg and from about 30% to about50% by weight of the tablet micronized tolcapone having a D_(v,0.9) ofnot more than 55 μm, (b) a cellulose polymer and (c) a binder, whereinthe tablet is coated and compressed and the proportion of tolcaponedissolved after 5 hours in the conditions of USP36 Tolcapone monographis not higher than 90% of the total amount of tolcapone in the tablet.2. A tablet according to claim 1 wherein the cellulose polymer isselected from the group consisting of cellulose ethers and celluloseesters.
 3. A tablet according to claim 2 wherein the cellulose polymeris hydroxypropyl methyl cellulose.
 4. A tablet according to claim 1wherein the binder is microcrystalline cellulose.
 5. A tablet accordingto claim 1 characterized in that it shows a release of tolcapone suchthat not greater than 90% is released during the period starting withoral ingestion and ending 5 hours after oral ingestion.
 6. A tabletaccording to claim 1 comprising tolcapone, hydroxypropylmethyl celluloseand microcrystalline cellulose.
 7. A tablet according to claim 6comprising tolcapone, hydroxypropylmethyl cellulose, microcrystallinecellulose, talc, magnesium stearate and anhydrous colloidal silica.
 8. Atablet according to claim 7 comprising by weight of the tablet: a) 30%to 50% tolcapone, b) 20 to 36% hydroxypropylmethyl cellulose, c) 36 to49% microcrystalline cellulose, d) 0.1 to 3% talc, e) 0.03 to 2%magnesium stearate, and f) 0.06 to 0.8% by weight of anhydrous colloidalsilica.
 9. A method for the treatment of a transthyretin-associatedamyloidosis comprising administering to a subject in need thereof aneffective amount of a tablet according to claim
 1. 10. A process for themanufacture of a tablet of claim 1 comprising: a) providing tolcapone, arelease retardant and a binder, b) optionally sieving the ingredients ofstep a) with a mesh having 5 mm openings, c) mixing the ingredients ofstep b), d) compressing the ingredients of step c) to form tablets, ande) coating the tablet.